As abdominal obesity increases in modern people due to the change in lifestyles, occurrence of metabolic diseases including diabetes, hypertension, dyslipidemia, insulin resistance, etc. is increasing rapidly. These diseases increase the risk of incidence one another and are commonly related to the cause of metabolic changes, such as aging, stress and suppressed immune system.
According to the 2005 Korea National Health and Nutrition Examination Survey, 32% of Korean adults aged 20 years or older turned out to be obese (35.2% of men and 28.3% of women). Infantile obesity is also increasing rapidly among Koreans. In 2005, 11.3% of elementary schoolchildren, 10.7% of middle school students and 16% of high school students were classified to be obese (BMI≧25 kg/m2), and 17% of overweight (BMI≧23 kg/m2) or obese teenagers had metabolic diseases.
Such increase in overweight and obese population leads to increased prevalence of chronic diseases. Actually, the prevalence of hypertension (30.2% in men and 25.6% in women), diabetes (9.0% in men and 7.2% in women) and hypercholesterolemia (7.5% in men and 8.8% in women) in Koreans aged 30 or older in 2005 was very high as compared to other countries. In 2005, deaths caused by diabetes in Korea were 35.5 per 100,000 people, 3-7 times more than those of Japan (5.9), England (7.5) or Germany (16.6). The number of Korean diabetic patients is expected to grow from 3,000,000 to 5,450,000 in 2030, meaning that 10% of Koreans will be diabetic patients.
According to the Korea Institute for Health and Social Affairs, the socioeconomic loss caused by obesity and obesity-related complications in 2006 is estimated at 2.1 trillion won including medical cost and indirect cost such as loss of earning. Thus, in 2010, the Korean government has decided to reduce the obesity rate down to 20% in men and 15% in youth, and is exploring ways to accurately define and diagnose obesity and metabolic diseases.
A lot of products for obesity treatment are imported from abroad and marketed in Korea. Among them, Xenical, Reductil and Exolise are well-known anti-obesity drugs. Xenical, which contains orlistat as main ingredient, is the world's first obesity treatment drug. It reduces absorption of fat by inhibiting lipase, and is effective in reducing total cholesterol and LDL cholesterol level, improving blood sugar and reducing blood pressure. Reductil, which contains sibutramine as main ingredient, was approved by FDA in 1997 and is marketed in more than 30 countries. The drug is effective in stimulating sympathetic nerves, reducing appetite and inducing satiety by keeping the level of serotonin and noradrenaline in the sympathetic nervous system high. And, Exolise is a non-prescription semiproduct imported from France. It increases body heat production and basal metabolic rate, and reduces fat absorption by about 30% by inhibiting lipase, and increase energy consumption by increasing the production of noradrenaline.
Although obesity can best treated by a combination of diet, exercise and behavior modification, it requires a lot of time and efforts and is difficult to put into practice. For this reason, obesity drugs or diet products are used a lot. However, orlistat is known to have side effects such as steatorrhea, production of bowel gas, abdominal inflation, etc., and sibutramine is known to have side effects such as headache, thirst, loss of appetite, insomnia, constipation, etc. Also, orlistat inhibits absorption of vitamin E and vitamin D, and phentermine and sibutramine can increase heart rate and cause tachycardia or dizziness.
Diabetes is caused by insufficient production or action of insulin. With prolonged metabolic disorder including hyperglycemia, it is highly likely to vascular complications. The number of diabetic patients is increasing consistently in tandem with the population aging and the change in lifestyles. In 1985, the number of diabetic patients in the world was 30 million, but is estimated at about 220 million in 2010. Particularly in industrialized countries, the number of diabetic patients is estimated to reach 10% of the total population. According to data from the Korea Institute of Science & Technology Evaluation and Planning, the global diabetes drug market is valued at about 11.8 billion dollars in 2005, increasing 12% year on year, and the US market of blood sugar measurement and insulin has grown from 2.6 billion dollars in 2004 to 3 billion dollars in 2005 by more than 15%. According to the IDF report, the global diabetes drug market is expected to grow by about 25% until 2025. And, according to the ADA report, the direct and indirect medical cost due to type 2 diabetes in the US in 2002 is estimated over 132 billion dollars.
While metformin- and thiazolidinedione (TZD)-based drugs as currently available type 2 diabetes drugs show considerable efficacy, they do not cure the fundamental cause of diabetes such as the onset of insulin resistance and several side effects are reported. Therefore, development of a more effective and safe drug capable of resolving the insulin resistance problem is necessary. At present, the ultimate aim of diabetic treatment is to consistently maintain a normal blood glucose level. It is because many animal and clinical experiments suggest that most diabetic complications are caused by metabolic disorders due to prolonged high blood glucose level and they can be prevented or delayed through strict control of blood sugar. Clinically used diabetes drugs can be classified largely into 1) drugs promoting the secretion of insulin, 2) drugs enhancing the sensitivity of insulin receptors, and 3) drugs suppressing glycolysis and thus reducing glucose absorption. Insulin exhibits the same physiological action as that in the body, but it has to be administered by injection and is associated with the insulin resistance problem. Sulfonylureas (glibenclamide, glipizide, gliquidone, etc.) are orally administrable and inexpensive, but they may induce hypoglycemia and loss of insulin-secreting ability. Biguanides (metformin, phenformin, etc.) suffer the problems of gastrointestinal side effects and nephrotoxicity. Glitazones (troglitazone, pioglitazone, rosiglitazone, etc.) were withdrawn from the market due to side effects such as heart failure, anemia, etc. Thus, development of medications ensuring both safety and efficacy is imminent.
As the synthetic drugs show limitations in side effects, new drugs derived from natural sources are drawing attentions. The inventors of the present disclosure have searched for obesity-suppressing active substances from plant sources and have taken notice of the monoterpene compound camphene, which is included in various plants.
Camphene is a constituent of essential oils from such plants as rosemary, camphor tree, nutmeg, tumeric, peppermint, ginger, pine tree, silver magnolia, cnidium, with molecular formula C10H16 and molecular weight 136.2. Camphene has long been used as food additive for flavoring. According to a recent report about the physiological activity of camphene, it has antioxidative, anti-inflammatory and antimicrobial activities (Antioxidative properties of the essential oil from Pinus mugo, J Argic Food Chem, 51(26): 7576-7582, 2003). Camphene has been proven to have anti-inflammatory effect by suppressing the activity of the inflammation-inducing factor NF-κB in mouse macrophage cells (RAW 264.7) (Anti-inflammation activity of fruit essential oil from Cinnamomum insularimontanum Hayata, Bioresource Technology 99: 8783-8787, 2008). Also, camphene has been shown to have antimicrobial activity by inhibiting growth of Gram-positive bacteria, Gram-negative bacteria and fungi (Chemical composition and antimicrobial activity of essential oil from cones of Pinus koraiensis, J Microbiol Biotechnol, 18(3): 497-502, 2008). Camphene is listed in the KFDA food additive database for use as flavoring agent and thus can be used as a.
U.S. Pat. No. 7,071,195 discloses a method for treating obesity using amine and amide derivatives acting as ligands for the neuropeptide Y Y5 receptor. U.S. Pat. No. 7,022,722 discloses thiazolidinedione analogs for the treatment of diabetes, hyperlipidemia or obesity.
U.S. Pat. No. 6,987,131 discloses compositions for treating hyperlipidemia, comprising phenylacetylglutamine, phenylacetylisoglutamine or phenylacetic acid. U.S. Pat. No. 6,942,967 discloses the use of the apobec-1 protein for targeting atherosclerosis, hyperlipidemia, obesity and diabetes.
Throughout the specification, a number of publications and patent documents are referred to and cited. The disclosure of the cited publications and patent documents is incorporated herein by reference in its entirety to more clearly describe the state of the related art and the present disclosure.